title: The Cag pathogenicity island and interaction between TLR2/NOD2 and NLRP3 regulate IL-1β production in Helicobacter pylori infected dendritic cells.
abstract: Helicobacter pylori colonization of the stomach affects about half of the world population and is associated with the development of gastritis, ulcers, and cancer. Polymorphisms in the IL1B gene are linked to an increased risk of H. pylori associated cancer, but the bacterial and host factors that regulate interleukin (IL)-1β production in response to H. pylori infection remain unknown. Using murine BM-derived DCs, we show that the bacterial virulence factors cytotoxin-associated genes pathogenicity island and CagL, but not vacuolating cytotoxin A or CagA, regulate the induction of pro-IL-1β and the production of mature IL-1β in response to H. pylori infection. We further show that the host receptors, Toll-like receptor 2 (TLR2) and nucleotide-binding oligomerization domain 2 (NOD2), but not NOD1, are required for induction of pro-IL-1β and NOD-like receptor pyrin domain containing 3 (NLRP3) in H. pylori infected DCs. In contrast, NLRP3 and the adaptor ASC were essential for the activation of caspase-1, processing of pro-IL-1β into IL-1β, and IL-1β secretion. Finally, we show that mice deficient in caspase-1, IL-1β, and IL-1 receptor, but not NLRP3, are impaired in the clearance of CagA-positive H. pylori from the stomach when compared with WT mice. These studies identify bacterial cag pathogenicity island and the cooperative interaction among host innate receptors TLR2, NOD2, and NLRP3 as important regulators of IL-1β production in H. pylori infected DCs.
authors.affiliation: Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA; World Class Institute, Korea Research Institute of Bioscience and Biotechnology, Ochang-Eup, Cheongwon-Gun, Choongbuk, Korea.
authors.forename: Dong-Jae
authors.initials: DJ
authors.lastname: Kim
authors.forename: Jong-Hwan
authors.initials: JH
authors.lastname: Park
authors.forename: Luigi
authors.initials: L
authors.lastname: Franchi
authors.forename: Steffen
authors.initials: S
authors.lastname: Backert
authors.forename: Gabriel
authors.initials: G
authors.lastname: Núñez
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000378:metabolism; D058491:Bacterial Load; D001426:Bacterial Proteins / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D003713:Dendritic Cells / Q000276:immunology* / Q000382:microbiology; D005786:Gene Expression Regulation / Q000235:genetics; D044404:Genomic Islands; D016481:Helicobacter Infections / Q000276:immunology*; D016480:Helicobacter pylori / Q000472:pathogenicity*; D007113:Immunity, Innate / Q000235:genetics; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics / Q000378:metabolism*; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism*; D014774:Virulence / Q000235:genetics
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D002352:Carrier Proteins; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D053473:Nod2 Signaling Adaptor Protein; C495945:Nod2 protein, mouse; D051195:Toll-Like Receptor 2; C074689:VacA protein, Helicobacter pylori; C080866:cagA protein, Helicobacter pylori; C568315:cagL protein, Helicobacter pylori
keywords: Helicobacter pylori; IL-1β; Inflammasome; NLRP3; NOD2